In mammals, ovulation is controlled by gonadotropins (luteinizing hormone and follicle-stimulating hormone) secreted by the pituitary and acting on the ovary. In addition to this hormonal control, the inventors have reported a role of neural control off ovulation (Lara H E, Dorfman M, Venegas M, Luza S M, Luna S L, Mayerhofer A, Guimaraes M A, Rosa ESAA, and Ramirez V D. Changes in sympathetic nerve activity of the mammalian ovary during a normal estrous cycle and in polycystic ovary syndrome: Studies on norepinephrine release. Microsc Res Tech 59: 495-502, 2002). Mammalian ovary receives a dense sympathetic innervation. These postganglionic sympathetic nerves originate from neuronal cell bodies of the ovarian ganglion and from cell bodies of the celiac and renal plexuses (Curry T E, Jr., Lawrence I E, Jr., Burden H W. Ovarian sympathectomy in the golden hamster: effects on estrous cyclicity and follicular development. Exp Clin Endocrinol. 1985; 86(3): 284-90, and Burden H W, Lawrence I E, Jr., Louis T M. The adrenergic innervation of the guinea pig ovary during prenatal and postnatal periods. Acta Anat (Basel). 1985; 122(3): 193-6). The ovary receives its sympathetic innervation from two sources: (a) the ovarian plexus nerve (OPN), which is associated with the ovarian branch of the uterine artery (Neilson D., Seegar Jones, G., Woodruff, J D., Goldberg, B. The innervation of the ovary. Obstetrical and Gynecological Survey, 1970; 25(1): 889-904, and (b) the superior ovarian nerve (SON), which is at least partially associated with the ligament of ovary (also known as the suspensory ligament or the infundibulopelvic ligament) (Lawrence I E, Jr., Burden H W. The origin of the extrinsic adrenergic innervation to the rat ovary. Anat Rec. 1980; 196(1): 51-9; and Neilson, supra)).
In general, the superior ovarian nerve fibers innervate preponderantly the secretory components of the ovary, i.e., interstitial glands and follicles, whereas the ovarian plexus nerve fibers are mostly perivascular (Lawrence, supra). Although there is some variation in the way that sympathetic nerves reach the ovary, no differences have been found in the intraovarian distribution of sympathetic fibers, which is similar in all mammalian species (although the density of the network varies considerably among them (Jacobowitz D, Wallach E E. Histochemical and chemical studies of the autonomic innervation of the ovary. Endocrinology. 1967, 81(5):1132-9.)). Norepinephrine is the main neurotransmitter present in the ovary (Lara H E, McDonald J K, and Ojeda S R. Involvement of nerve growth factor in female sexual development. Endocrinology. 1990; 126(1): 364-75, Greiner M, Paredes A, Araya V, Lara H E. Role of stress and sympathetic innervation in the development of polycystic ovary syndrome. Endocrine. 2005; 28(3): 319-24, and Lara et al 2002, supra). The innervation of the gland has been shown to be involved in the regulation of ovary specific functions, such as steroidogenesis and early follicular development (Greiner et al, supra, and Lara et al, 2002, supra) by activating B-adrenergic receptors present in cells of the ovarian follicle.
Transection of the superior ovarian nerve, which carries the bulk of the sympathetic innervation to ovarian endocrine cells has been observed to restore estrous cyclicity and ovulation (Ovarian steroidal response to gonadotropins and beta-adrenergic stimulation is enhanced in polycystic ovary syndrome: role of sympathetic innervation; Barria A, Leyton V, Ojeda S R, Lara H E; Endocrinology. 1993 December; 133(6):2696-703). In contrast, a sustained increase in sympathetic activity by estradiol administration (1), chronic sympathetic stress (2), or pharmacological β-adrenergic receptor activation (3) causes the appearance of a polycystic phenotype in the rat ovary, which in many aspects resembles the polycystic ovary syndrome in women (1—Lara H E, Dissen G A, Leyton V, Paredes A, Fuenzalida H, Fiedler J L, and Ojeda S R. An increased intraovarian synthesis of nerve growth factor and its low affinity receptor is a principal component of steroid-induced polycystic ovary in the rat. Endocrinology 141: 1059-1072, 2000; 2—Dorfman M, Arancibia S, Fiedler J L, and Lara H E. Chronic intermittent cold stress activates ovarian sympathetic nerves and modifies ovarian follicular development in the rat. Biol Reprod 68: 2038-2043, 2003; and 3—Luna S L, Neuman S, Aguilera J, Brown D I, and Lara H E. In vivo β-adrenergic blockade by propranolol prevents isoproterenol-induced polycystic ovary in adult rats. Horm Metab Res 44: 676-681, 2012).
Polycystic ovary syndrome (PCOS) is often characterized by hyperandrogenism and a build-up of fluid-filled follicles (cysts), which do not undergo rupture during their normal maturation cycle. PCOS is the most prevalent ovarian pathology in women, affecting 5% to 12% of women of reproductive age, leading to endocrine/metabolic disorder. One of the principal symptoms of PCOS is anovulation, resulting in irregular menstruation and infertility. In addition, androgen secretion by the cysts in PCOS patients leads to masculinizing effects, such as acne and hirsutism. Recently, suppression of sympathetic activity by acupuncture was found to reduce the PCOS symptoms (Stener-Victorin E, Jedel E, and Manneras L. Acupuncture in polycystic ovary syndrome: current experimental and clinical evidence. J Neuroendocrinol 20: 290-298, 2008).
Current treatment of PCOS principally involves lifestyle changes such as weight loss and exercise, and as such PCOS presents a significant unmet medical need. Current treatment options focus on the symptoms, rather than the underlying cause, which is multi-factorial and not fully understood. For example, estrogen receptor modulators (e.g. clomiphene and metformin) and gonadatotrophins may be prescribed to induce regular cycling and ovulation, and laparoscopic ovarian drilling may be used to destroy the ovarian tissue that produces androgens. The fact that the pharmacological approach is principally focused to restore the function of reproductive hypothalamus, and the surgical procedure is focused at the ovary, means that the real cause could involve the complete organism and the brain-ovary connection.
WO2013/134548 proposes ovarian neuromodulation as a treatment for PCOS. More particularly, the inventors propose the destruction or ablation of the nerves adjacent to the ovarian blood vessel with a neuromodulation assembly which is intravascularly positioned within an ovarian blood vessel, although the examples section WO2013/134548 relate to a different intervention (renal neuromodulation) and show no indication of a positive treatment effect of this procedure (or indeed ovarian nerve ablation) on PCOS symptoms. However, this approach may also affect ovarian blood flow through the ovarian artery (Hotta, H. et al. J. Physiolol. Sci. 2008 58(2): 133-138), modulating the exposure of the ovary to circulating hormones from the hypothalamus and pituitary.